TREATMENT OF MELANOMA AND BREAST CANCER WITH GENETIC BASED LIPOSOMAL DRUG FORMULATIONS
Open Access
- Author:
- Tran, Melissa Ann
- Graduate Program:
- Genetics
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- February 28, 2008
- Committee Members:
- Gavin Peter Robertson, Committee Chair/Co-Chair
Craig Matthew Meyers, Committee Member
Laura Carrel, Committee Member
Jiyue Zhu, Committee Member
Thomas Loughran, Committee Member - Keywords:
- siRNA
liposomes
melanoma
ultrasound - Abstract:
- Treatment options for patients with cancers such as breast carcinoma and melanoma are poor with early detection as the best therapy. For patients with advanced stage disease, treatments are limited and outcomes poor. Development of therapies that target key pathways are needed such as targeting the PI3k/Akt and Map kinase pathways. It was found that targeting these pathways in combination, with sorafenib and nanoliposomal ceramide, results in greater melanoma and breast tumor inhibition than targeting only one pathway. In vivo, a ~30% increase in tumor inhibition compared to sorafenib treatment alone and a ~58% reduction in tumor size compared to nanoliposomal ceramide monotherapy occurred by doubling apoptosis rates with negligible systemic toxicity. This was followed by utilization of an siRNA-based approach to further evaluate the potential of targeting these pathways in combination. siRNA-based therapies have great potential for use in combination therapies but appropriate targets and effective delivery systems are required. B-Raf is mutated in ~60% of melanomas leading to constitutive activation of the Map kinase pathway making it an attractive target for siRNA therapy. Therefore, a novel liposome formulation was designed that efficiently loaded and delivered mutant V600EB-Raf siRNA to melanoma cells. Systemic administration of siMutB-Raf-liposomal complexes led to a ~ 25% reduction in tumor growth in a mouse xenograft model of melanoma. Additionally, localized topical administration of siMutB-Raf-liposomal complex in conjunction with ultrasound treatment resulted in tumor reduction in both a three-dimensional skin model and in mice with melanoma xenografts. Furthermore, adding siRNA to Akt3 in a liposomal formulation to the topically applied siMutB-Raf-liposomal complex doubled tumor inhibition to 60%. These studies demonstrate the potential utility of targeting multiple cancer pathways both by pharmacological means and via siRNA. Designing a novel liposome formulation to encapsulate siRNAs advanced the use of siRNA as a therapeutic in melanoma. Furthermore, this liposomal siRNA complex can be modified in the future to improve the results seen here. These studies demonstrate the use of siMutB-Raf-liposomal complexes alone or in combination with siAkt3-liposomal complexes in the treatment of melanoma. Additionally the use of siRNA as a topical agent was advanced by using ultrasound to transiently permeabilize the skin followed by addition of siRNA liposomal complexes. Thus, targeting the PI3k/Akt pathway in conjunction with the Map kinase pathway is potentially useful for targeting melanoma and breast cancer.